tbuckley/cabot-search huggingface dataset:
Plasma methylated DNA markers detect recurrence and response to therapy in colorectal cancer.
Authors: Mojun Zhu, William R. Taylor, Douglas W. Mahoney, Sara S. Then, Calise K. Berger, Kelli Burger, Anna M. Gonser, Karen A. Doering, Patrick H. Foote, Michael W. Kaiser, Hatim T. Allawi, Joleen M. Hubbard, John B. Kisiel
Journal: Journal of Clinical Oncology (2022)

e15567 Background: Radiographic surveillance of colorectal cancer (CRC) after therapy is costly and insensitive. We have reported high cross-sectional performance of methylated DNA markers (MDMs) for detection of primary CRC and metastatic recurrence. This study evaluated MDMs to detect recurrence and measure response to anti-cancer therapy in a longitudinal cohort. Methods: This was a nested case-control study drawn from a prospective cohort of adult patients with CRC who completed definitive treatment and followed forward from the start of surveillance by cross-sectional imaging (CT or MRI) and carcinoembryonic antigen (CEA), collected every 3-6 months under routine care. Blood was collected in LBgard® tubes (Biomatrica, San Diego CA). Cases had recurrent CRC (defined by RECIST v1.1 or radiographic findings that justify re-initiation of anti-cancer therapy as determined by treating clinicians). Controls remained NED (no radiographic recurrence and off therapy for ≥4 surveillance visits). From 6mL of plasma, MDMs ( CNNM1, ANKRD13B, FER1L4, ZNF568, CHST2, ZNF671, VAV3, QKI, GRIN2D, DTX1, PDGFD, SFMBT2, JAM3) were measured by target enrichment long-probe quantitative-amplified signal assays, normalized to B3GALT6, in blinded fashion. Previously published random forest models of MDMs +/- CEA, developed on independent patients with intact primary tumors, were used to develop a summary score. Results: With a median follow-up of 276 days (IQR 187-343) and 3 visits per patient (54 visits total), 18 patients had recurrence after start of surveillance. Another 18 patients remained NED after median 555 days (IRQ 469-662) and 4 surveillance visits per patient (76 visits total). Using a 90 th %-ile cut-off summary score from 60 NED patients in a prior cross-sectional measurement, the MDM panel was positive in 15 of 18 patients who recurred and only 2 of the 18 NED patients (Table). Of the 76 patient visits for NED patients, 67 (88%) were below the threshold. The MDM panel score crossed the positivity threshold by a median of 127 days (IRQ 0-233) preceding clinical or radiographic documentation of recurrence. A random forest model with CEA was more sensitive but less specific (Table). In patients who resumed therapy, the MDM panel scores correlated closely with subsequent RECIST scores (not shown). Conclusions: Plasma MDMs rise in anticipation of recurrent CRC prior to radiographic detection and remain low in patients without radiographic disease over serial measurements, warranting further development of this tumor-agnostic liquid biopsy approach as a cost-effective tool to assist cancer surveillance.[Table: see text]
Economic evaluations of adjunctive osimertinib treatment in surgically resected epidermal growth factor receptor positive (EGFR+) non-small cell lung cancer (NSCLC): Analysis for stage 1B disease.
Authors: Briana M Choi, Rachel B Abraham, Osama Aqel, Uche S Agu, Kristen C. Gregory, Mavis Obeng-Kusi, Matthias Calamia, Hala Halawah, Deniz Tugay, Ahmad Alamer, Ali McBride, Ivo Abraham
Journal: Journal of Clinical Oncology (2022)

e20502 Background: Patients with stage 1B non-small cell lung cancer (NSCLC) who receive surgical resection are at continued risk of disease recurrence and death after the surgery. Osimertinib, a tyrosine kinase inhibitor indicated for epidermal growth factor receptor positive (EGFR+) NSCLC, has been used post-operatively as adjunctive therapy to improve clinical outcomes in surgically resected EGFR+ stage 1B NSCLC. We evaluated the cost effectiveness/utility of adjunctive osimertinib treatment post-surgically in stage 1B. Methods: A two state partitioned survival model with disease free survival (DFS) and disease recurrence or death was specified (US payer perspective). Kaplan-Meier DFS curves were fitted to parametric functions. A 5 year time horizon was adopted and a 3% discount rate was applied to costs and utilities after year 1. Wholesale acquisition costs for treatments were sourced from Redbook, adverse event costs (grade 3/4; all grades for immunotherapy related AEs) utilized published data, and monitoring costs were based on Physician Fee Schedules (US $2021). We estimated incremental costs, DFS life years (DFSLY), and DFS quality adjusted life years (DFSQALY). Based on DFSLY and DFSQALY gained (g), incremental cost effectiveness/utility ratios (ICER/ICUR) were determined in base case analyses (BCA) and probabilistic sensitivity analyses (PSA). Results: Exponential regression was utilized to extrapolate the osimertinib DFS Kaplan-Meier curve, while Weibull regression was applied for extrapolation of the placebo DFS curve. Shown in the table below, the BCA (PSA) revealed incremental cost of $774,710 ($775,941) and ncremental DFSLY of 0.813 (0.954), yielding an ICER of $952,797/DFSLYg ($813,162/DFSLYg); and incremental DFSQALY of 0.576 (0.676), yielding an ICUR of $1,345,340/DFSQALYg (1,147,793/DFSQALYg). Conclusions: In surgically resected stage 1B EGFR+ NSCLC, the model estimated incremental benefits of 0.813 (0.954) LYg and 0.576 (0.676) QALYg, however at marked incremental cost. As adjunctive osimertinib treatment is indicated in EGFR+ NSCLC disease stages 2 and 3A, the present stage 1B cost effectiveness/utility results should be compared to those for stages 2 and 3A.[Table: see text]
Addressing cancer health disparities (CHD) in an independent community cancer clinic: All solutions are local.
Authors: Natasha Clinton, Kashyap B. Patel, Asutosh S. Gor, Viral Rabara
Journal: Journal of Clinical Oncology (2022)

e18522 Background: The COVID-19–associated global pandemic has brought many public and population health issues to light. A glaring issue is the disparities among and differences in susceptibility of diverse ethnicities. Viral infection is not the only area of healthcare facing this issue: disparities in prevalence, biology, prognosis, and outcomes of cancer exist, often based on socioeconomics and social determinants of health (SDoH). CHD have been debated and discussed at several levels, from local counties to the congress to the Centers for Medicare and Medicaid Services. Amid the debates and recommendations, it has been difficult to carve out a clear path forward. The complex factors involved include access to care because of financial challenges, biological and genetic factors, impact of SDoH, and access to screening, NGS testing, and clinical trials. CHD may contribute to almost 34% of deaths among adult cancer patients and additional spending of $230 billion. Addressing CHD could result in an indirect savings of as much as $1 trillion over 3 years (AACR, CDR, 2020). A comprehensive approach is needed to generate a groundswell of resources. This should include support for public policies aimed at improving understanding of the issue by all parts of the ecosystem (pharma, researchers, government agencies, physicians), adequate funding for federal and local initiatives, considerations of health in community planning and development, and collection of real-world data and evidence. At Carolina Blood and Cancer Care (CBCCA), the team decided to study this issue and initiate solutions one step at a time. Methods: CBCCA prioritized solutions in 5 categories. The top priority was to address issues impacting patients: access to care, NGS testing, cancer screening, SDoH, and clinical trial access. To address access to care issue (financial constraints), 2.5 FTEs (full-time equivalents) were allocated to carry out needs assessments and identify resources, including Medicaid eligibility, dual eligibility, other foundations, and sources for free drugs. A not-for-profit entity, No One Left Alone, was started to address CHD. Results: During 2021 CBCCA physicians saw 1787 unique cancer patients (both established and new). Of these, 319 needed IV anticancer treatment and an additional 104 needed oral oncolytics. Fifty-three could not pay for their cancer treatment. Another 101 patients needed assistance for out-of-pocket costs. Financial counselors procured free drugs worth $1,633,588 and an additional $135,931 in cash assistance for high out-of-pocket costs. The pharmacy team raised $253,218 for 64 patients (374 transactions) for out-of-pocket costs. As a result, not a single patient was left without treatment. Conclusions: Financial toxicity was addressed by allocating 0.5 FTE per oncologist to ensure access to care. In the next phase, CBCCA will address access to NGS testing.
Demonstration of the value of liquid biopsy to identify metastatic breast cancer: Comparison and combination of cell and cell-free platforms.
Authors: Giuseppe Di Caro, David Bourdon, Jiyun Byun, Tatjana Singer, Amanda Anderson, Alisa Tubbs, Martin Blankfard, Rick Wenstrup
Journal: Journal of Clinical Oncology (2022)

e13004 Background: Liquid biopsy analysis detecting circulating tumor cells (CTC) or circulating tumor DNA (ctDNA) is a non-invasive approach that may provide clinically actionable information for patients’ (pts) treatment decisions when conventional biopsy is otherwise inaccessible or infeasible. Here we report a liquid biopsy analysis method including CTC characterization and ctDNA alterations in late-stage metastatic breast cancers (MBC). Methods: Blood samples were collected for cell and cell-free DNA analysis from 57 pts with MBC. 44 pts were progressing on treatment and 13 were responding to treatment. Blood was also collected from 25 blood donors (HD) with no known cancer history. After plasma isolation, nucleated cells were plated, and slides were bio-banked. Immunofluorescent staining and subsequent imaging were performed on replicate slides. CTCs were identified using Epic Sciences digital imaging and machine learning algorithms trained to identify breast cancer cells. Single-cell (sc) isolation for genomic quantification of large-scale transitions (scLST) was used to further characterize individual CTCs. cfDNA from bio-banked plasma was analyzed using a validated NGS panel to detect class 1A ctDNA alterations. Results: Within this cohort of 57 MBC pts, CTCs, scLST+CTCs and ctDNA alterations were detected in (77%, 49% and 33%, respectively). All MBC pts on active therapy (23%) had no CTC detected. No CTCs, scLST+CTCs or ctDNA were detected in the HD cohort, suggesting high specificity (100%, 100% and 100%, respectively). The presence of CTCs or of scLST+CTCs had low concordance with the presence of ctDNA+ alterations in MBC pts, suggesting that these platforms provide independent and complementary value when identifying MBC. To test this hypothesis, we designed combination models which added ctDNA to cell analysis methods ([CTC+][ctDNA+] and [scLST+CTC+][ctDNA+]). Adding ctDNA to either cell analysis method increased sensitivity by 5% and 12%, respectively, over the individual methods and retained 100% specificity. Conclusions: Here we demonstrate the value of comprehensive cell and cell-free liquid biopsy analysis for the detection of MBC pts. Our data suggest there may be clinical utility of adding cell-free to cell analysis for the identification of MBC. Analysis of the comparative and combined utility of these liquid biopsy methods in earlier settings is ongoing.
Real-world outcomes and prognostic factors in uterine leiomyosarcom: A single center experience from India.
Authors: Upasana Palo, Arunava Roy, Anik Ghosh, Debapriya Mondal, Basumita Chakraborti, Jaydip Bhaumik
Journal: Journal of Clinical Oncology (2022)

e17620 Background: Uterine leiomyosarcoma (uLMS) is a rare and aggressive malignancy with dismal prognosis, often diagnosed incidentally after surgery for presumed benign disorders. There is a dearth of prospective data particularly in Indian women owing to its rarity. Published studies differ about prognostic factors, and the role of adjuvant treatment in uLMS. Methods: Prospectively maintained uterine cancer electronic database was used to include uLMS patients with adequate clinical information who underwent treatment between January 1, 2012 and December 31, 2021. Progression-free survival (PFS) and overall survival (OS) were calculated for the entire population, while recurrence-free survival (RFS) was calculated for the patients who had curative intent treatment. Various potential prognostic factors were tested using univariate and multivariate analysis. Results: Among 44 identified patients of uLMS, 32 women with sufficient information were included in the study. Majority of the patients had early stage disease at diagnosis including 19 (59.4%) patients with FIGO stage I tumors. Twenty three (71.9%) patients were diagnosed incidentally after surgery. Curative intent treatment was offered to 26 patients (81.3%) while 6 (18.7%) patients had palliative treatment. Median tumor size was 9 cm (interquartile range [IQR] 7-15), and the median mitotic count was 16 per 10 high power fields (hpf) (IQR, 12-25). Eleven patients (34.3%) received adjuvant chemotherapy while 15 patients (46.9%) remained on surveillance. After a median follow-up of 63.8 months, 22 patients (68.8%) had disease recurrence and 23 (71.9%) patients had died. Lung was the most common site (64.3%) of recurrence, followed by bone (18.8%), and abdominal cavity (12.5%). The median PFS and OS for the whole population were 20.7 months (95% confidence interval [CI] 13.7 - 27.7) and 28 months (95% CI 19.7 - 36.3) respectively. The 5-year PFS estimate was 20% while the 5-year survival probability was 25%. Stage specific 5-year OS probabilities for stage I, II, III, and IV were 45%, 40%, 20%, and 8% respectively. Patients who received adjuvant chemotherapy had longer RFS than those who were observed after primary surgery (median 59·9 months [95% CI 19.5–100.3] vs 20.5 months [95% CI 15.8-25.3]; hazard ratio [HR] 0·13 [95% CI 0.02-0.85; p = 0·03). Lower stage (FIGO stage I-II) (HR 0.15 [95% CI 0.03-0.67]; p = 0.013), and lower mitotic count (&lt; 15/10 hpf) (HR 0.13 [95% CI 0.03-0.61]; p = 0.01) were independent prognostic factors associated with better survival. Conclusions: This 10-year experience of uLMS from an Indian tertiary care cancer center shows poor survival across stages with a high rate of recurrence. Only stage and mitotic count were found to be independent prognostic factors. The finding of RFS benefit with adjuvant chemotherapy warrants larger prospective studies to evaluate the role of adjuvant therapy in uLMS.
Modeling of an SCN5A founder mutation in iPSC-derived cardiomyocytes
Authors: E Simons, A Nijak, B Vandendriessche, D Van De Sande, E Sieliwonczyk, A J Labro, J Saenen, D Snyders, D Schepers, B Loeys, M Alaerts
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Research Foundation - Flanders (FWO) Introduction SCN5A encodes the α-subunit of voltage-gated cardiac sodium channel Nav1.5. Mutations in SCN5A are identified in about 20% of patients with Brugada syndrome (BrS), an inherited cardiac arrhythmia. We have identified an SCN5A founder mutation (c.4813+3_4813+6dupGGGT), leading to a loss-of-function of Nav1.5 in 25 different families. Mutation carriers show variable expression of the phenotype: from asymptomatic to syncopes and sudden cardiac death. We used induced pluripotent stem cell derived cardiomyocytes (iPSC-CM) to investigate the underlying pathophysiology. Material &amp; Methods Dermal fibroblasts of six patients with different disease severity, and two unrelated healthy control individuals were reprogrammed using a commercially available reprogramming kit. iPSC-CMs were differentiated following a published protocol. We performed several differentiation rounds and investigated expression of cardiac markers using qPCR and immunocytochemistry and electrophysiological properties using patch-clamping. Results All iPSC-CMs expressed the tested markers. We observed reduction in sodium current density in patient iPSC-CMs compared to the control cells. However, our data display variability in AP characteristics between the differentiation batches, as well as between clones generated from one donor. Conclusions We established iPSC-CM models for a unique Belgian SCN5A founder mutation. Despite the observed variability, we could detect expected differences in electrophysiological properties of patient cells compared to controls.
Securing access to innovative anticancer therapies for children, adolescents, and young adults outside clinical trials: The SACHA study of the French Society of Pediatric Oncology (SFCE).
Authors: Pablo Berlanga, Lee Aymar Ndounga-Diakou, Nadege Corradini, Stephane Ducassou, Marion Strullu, Emilie De Carli, Nicolas Andre, Natacha Entz-Werle, Anne Sophie Defachelles, Marianne Roumy, Dominique Valteau-Couanet, Virginie Gandemer, Salim Laghouati, Gilles Vassal
Journal: Journal of Clinical Oncology (2022)

10006 Background: Access to innovative anticancer therapies for children, adolescents and young adults within clinical trials in France is steadily increasing in the last years. However, current clinical trials portfolios are still inadequate and thus pediatric hemato-oncologists regularly prescribe innovative medicines outside their marketing authorization, and/or experimental drugs through compassionate use. Methods: The Secured Access to innovative medicines for CHildren with cAncer (SACHA) is a French prospective observational study developed by the French Society of Pediatric Oncology (SFCE) with Gustave Roussy as the legal sponsor to prospectively collect real-world safety and activity data of innovative therapies administered to patients ≤ 25 years-old with pediatric malignancies (solid tumor or leukemia) or other related conditions, either on compassionate use of experimental drugs or off-label use of anti-cancer medicines that have been first approved in adults after 2007. Prior to SACHA inclusion, multicenter tumor board discussion defining best available therapeutic options for each patient with a relapsed malignancy is mandatory. Results: The SACHA study opened in March 2020 and by February 2022, 283 patients have been included from 29/31 SFCE recruiting centers; median age: 11.0 years (range: 0.3-24.4). Main cancer types were central nervous system (CNS) tumors (47%), followed by non-CNS tumors (40%) and leukemias (13%). Innovative therapies prescribed in &gt; 10 patients with reported objective response rate (ORR) and related CTCAE v.5 grade ≥2 clinical and/or grade ≥3 biological adverse drug reactions (ADRs) are described in Table. Conclusions: SACHA confirms the feasibility of this type of prospective real word registry, with a high participation of French centers. Based on this French experience, the Innovative Therapies for Children with Cancer (ITCC) consortium is currently developing a “SACHA International Project” to be opened in ITCC and collaborating countries. [Table: see text]
Detection of SARS-CoV-2 in young children attending day-care centres in Belgium, May 2020 to February 2022
Authors: Liesbet Van Heirstraeten, Esra Ekinci, Mathias Smet, Matilda Berkell, Laura Willen, Jasmine Coppens, An Spiessens, Basil Britto Xavier, Christine Lammens, Jan Verhaegen, Pierre Van Damme, Herman Goossens, Philippe Beutels, Veerle Matheeussen, Stefanie Desmet, Heidi Theeten, Surbhi Malhotra-Kumar
Journal: Eurosurveillance (2022)

Presence of SARS-CoV-2 was monitored in nasopharyngeal samples from young children aged 6-30 months attending day-care centres (DCCs) in Belgium from May 2020-February 2022. SARS-CoV-2 carriage among DCC children was only detected from November 2021, after emergence of Delta and Omicron variants, in 9 of the 42 DCCs screened. In only one DCC, two children tested positive for SARS-CoV-2 at the same sampling time point, suggesting limited transmission of SARS-CoV-2 in Belgian DCCs among young children during the studied period.
Economic evaluations of adjunctive osimertinib treatment in surgically resected epidermal growth factor receptor positive (EGFR+) non-small cell lung cancer (NSCLC): Analysis for stage 3A disease.
Authors: Mavis Obeng-Kusi, Briana M Choi, Rachel B Abraham, Osama Aqel, Matthias Calamia, Hala Halawah, Deniz Tugay, Ahmad Alamer, Ali McBride, Ivo Abraham
Journal: Journal of Clinical Oncology (2022)

e20505 Background: Patients with surgically resected EGFR+ NSCLC remain at risk of recurrence after surgery. Osimertinib, a tyrosine kinase inhibitor, had been assessed clinically as adjunctive therapy in surgically resected EGFR+ NSCLC including stage 3A. We conducted a cost effectiveness/utility analysis of adjunctive osimertinib therapy in stage 3A surgically resected EGFR+ NSCLC. Methods: We specified a two state partitioned survival model of disease free survival (DFS) versus disease recurrence and death in a), with a 5 year time horizon (US payer perspective). DFS and overall survival curves were extrapolated per parametric functions. A 3% discount rate was utilized to costs and utilities beyond year 1. Costs of therapies (wholesale acquisition cost), adverse events (AE; grade 3/4; all grades for immunotherapy related AEs), and monitoring costs were based on Redbook, publications, and Physician Fee Schedules, respectively (US $2021). Costs, DFS life years (DFSLY) and DFS quality adjusted life years (DFSQALY) were used to determine the incremental cost effectiveness/utility ratios (ICER/ICUR) of the additional cost needed to gain (g) a DFSLY and DFSQALY in base case (BSA) and probabilistic sensitivity analyses (PSA). Results: Exponential regression was used to extrapolate the Kaplan-Meier curves of osimertinib and placebo,. As shown in the table, the BCA (PSA) estimated the incremental cost at $669,369 ($670,274). The incremental DFSLY was 1.895 (1.899), yielding ICER of $353,125/DFSLYg ($352,963/DFSLYg). The incremental DFS QALY was 1.35, yielding an ICUR of $497,905/DFSQALYg ($497,676/DFSQALYg). Conclusions: In stage 3A surgically resected EGFR+ NSCLC, adjunctive osimertinib therapy showed incremental benefits of 1.895 (1.899) DSFLYg and 1.344 (1.349) QALYg compared to placebo, however at marked incremental cost. As adjunctive osimertinib treatment is indicated in EGFR+ NSCLC disease stages1B and 2, the present stage 3A cost effectiveness/utility results should be compared to those for stages 1B and 2.[Table: see text]